RESUMO
The endogenous lipid signaling agent oleoylethanolamide (OEA) has recently been described as a peripherally acting agent that reduces food intake and body weight gain in rat feeding models. This paper presents evidence that OEA is an endogenous ligand of the orphan receptor GPR119, a G protein-coupled receptor (GPCR) expressed predominantly in the human and rodent pancreas and gastrointestinal tract and also in rodent brain, suggesting that the reported effects of OEA on food intake may be mediated, at least in part, via the GPR119 receptor. Furthermore, we have used the recombinant receptor to discover novel selective small-molecule GPR119 agonists, typified by PSN632408, which suppress food intake in rats and reduce body weight gain and white adipose tissue deposition upon subchronic oral administration to high-fat-fed rats. GPR119 therefore represents a novel and attractive potential target for the therapy of obesity and related metabolic disorders.
Assuntos
Depressores do Apetite/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Ácidos Oleicos/metabolismo , Ácidos Oleicos/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Animais , Depressores do Apetite/administração & dosagem , Depressores do Apetite/química , AMP Cíclico/metabolismo , Dieta , Relação Dose-Resposta a Droga , Endocanabinoides , Humanos , Masculino , Camundongos , Dados de Sequência Molecular , Obesidade/tratamento farmacológico , Ácidos Oleicos/administração & dosagem , Ácidos Oleicos/química , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/genética , Especificidade por Substrato , Fatores de Tempo , Leveduras/metabolismoRESUMO
The synthesis, SAR and biological evaluation of a series of ureas that activate glucokinase, a target for diabetes therapy as a result of its critical role in the regulation of whole-body glucose homeostasis, are described. Some of the urea-containing glucokinase activators lowered blood glucose levels in vivo following oral dosing to C57BL/6J mice.